1. Field of the Invention
This invention relates to novel compounds for CNS neurotransmitter systems especially for the neurotransmitter serotonin, which can be utilized to image neurotransmitter reuptake systems in the brain.
2. Related Art
Depression, with its related conditions, is one of the most common mental disorders in the United States. It is estimated that about five percent of the adult population experiences a depressive episode in their lifetime that requires antidepressive drug therapy. A chemical in the human brain, called serotonin, has been linked with depression and with other psychiatric disorders such as eating disorders, alcoholism, pain, anxiety and obsessive-compulsive behavior.
Serotonin (5-FT) is an essential neurotransmitter for the normal function of the central nervous system. This neurotransmission system in the brain controls various important behaviors, including sleep awake cycle, mood, temperature, appetite, etc. In addition, several commonly used anti-anxiety drugs (Frazer, A. and J. G. Hensler, Ann. NY Acad. Sci. 600:460-475 (1990); Gozlan, H. and M. Hamon, Anxiety: Neurobiol., Clinic and Ther. Persp. 232:141-150 (1993)) and antidepressants (Frazer, A., J. Clin. Psychiatry 6:9-25 (1997), Coryell, W., J. Clin Psychiatry 1:22-27 (1998); Heninger, G. R. et al., Pharmacopsychiatry 29(1):2-11 (1996); Fuller, R. W., Prog. Drug Res. 45:167-204 (1995)) interact specifically with serotonin neurotransmission. Pharmacological actions of the antidepressants (selective serotonin reuptake inhibitors; SSRI), such as fluoxetine (Wong, D. T. and F. P. Bymaster, Biology 363:77-95 (1995)), paroxetine (Holliday, S. M. and G. L. Plosker, Drugs Aging 3(3)278-299 (1993)) and sertraline (Lasne, M. C. et al., Int. J. Rad Appl. Inst.—Part A, Applied Rad Isot. 40(2):147-151 (1989)), are based on blockade of presynaptic transporters serotonin. Thus, studies of radioligand binding to serotonin transporter (SERT) may provide valuable information of these sites in normal and various disease states. Several tritiated ligands including imipramine (Raisman, R. et al. Eur. J. Pharmacol. 54:307-308 (1979)), citalopram (D'Amato, R. et al. Pharmacol. Exp. Ther. 242(1):364-371 (1987)), paroxetine (Habert, E., et al. Eur. J. Pharmacol. 118(1-2):107-114 (1985)) and 6-nitroquipazine (Hashimoto, K., and T. Goromaru, Biochem. Pharmacol. 41(11):1679-1682 (1991); Hashimoto K, and T. Goromaru, Neuropharmacology 30(2):113-117(1991)) have been used for in vitro and in vivo studies. A reduced level of SERT labeled by these tritiated ligands has been demonstrated in post mortem brain sections of patients with depression (Perry, E. K. et al, Br. J. Psychiat. 142:188-192 (1983)), Alzheimer's and Parkinson's diseases (D'Amato, R. et al., Pharmacol. Exp. Ther. 242(1):364-371 (1987)) as well as in the frontal cortex of a suicide victim (Mann, J. J., Nature Medicine 4(1):25-30 (1998)). The in vitro binding studies suggest that using in vivo imaging methods to evaluate the density of SERT may be clinically important.
Anti-depressive drugs, such as Prozac, operate to inhibit serotonin reuptake by binding with the serotonin transporter (SERT) protein, effectively blocking the binding of the protein with serotonin. Although Prozac has been found to be an effective anti-depressant treatment, it has side effects which can be serious. Prozac is known to bind to the serotonin transporter (SERT) protein, but the responses of patients can differ widely. Some patients experience greater binding than others. If a patient is not responding to Prozac treatment, there is currently no way to determine why that is the case. Frequently, the physician will simply administer greater doses of the drug, a practice which will not necessarily lead to better results and which can enhance undesirable side effects.
Development of selective tracers for positron emission tomography (PET) and single photon emission tomography (SPECT) have made it possible to study in vivo neuroreceptors or site-specific bindings non-invasively in the human brain. However, development of PET or SPECT tracers specifically for in vivo imaging of SERT has only met with limited success. The most promising radioligand described to date is [11C](+)McN5652 for PET imaging (Szabo, Z. et al., Synapse 20(1):37-43 (1995); Szabo, Z. et at., J. Nucl. Med. 37(5):125 (1996); Szabo. Z. Behav. Brain Res. 73(1):221-224 (1995); Szabo, Z. et al, J. Cerebral Blood Flow & Metabol. 15(5):798-805 (1995); Suehiro, M. et al., J. Nucl. Med. 34(1): 120-127 (1993); Suehiro, M. et al., Nucl. Med. Biol 22(4):543-545 (1995)). Specific binding of [11C](+)McN5652 correlates well with the known density of SERT sites in the human brain (Szabo, Z. et al., Synapse 20(1):3743 (1995)). In search of a clinically useful SPECT ligand for SERT, several radioiodinated compounds have been evaluated including 4-I-tomoxetine (Kung, M. P. et al., Life Sci. 51:95-106 (1992)). Among these tracers only [I23I]5-iodo-6-nitroquipazine (Biegon, A. et al., Brain Res. 619:236-246 (1993); Mathis, C. A. et at, Brain Res. 619:229-235 (1993); Mathis, C. A. et al., Eur. J. Pharmacol 210(1):103-104 (1992)) showed promising properties for mapping SERT sites in monkey's brain (Jagust, W. J. et al., J. Nucl. Med. 37(7):1207-1214 (1996)). No human study of [123I]5-iodo-6-nitroquipazine has been reported. The high nonspecific binding and the fast peripheral metabolism observed with [123I]-5 iodo-6-nitroquipazine in non-human primates may limit its application as a clinically useful SPECT imaging agent for SERT in the human brain. Previously, it has been suggested that [123I]β-CIT(2β-carbomethoxy-30-(4-iodophenyl)tropane), a SPECT imaging agent, which binds to both DAT and SERT, will be able to clarify pathological changes in both dopaminergic and serotonergic systems. However, overlapping uptake regions and differential kinetics of [1231]-CIT binding to DAT and SERT were observed (Fujita, M. et al., Eur. J. Nucl. Med. 23(4):431-436 (1996); Kuikka, J. T. et al., Eur. J. Nucl. Med. 22(4):346-250 (1995); Tiihonen, J. et al., Eur. J. Nucl. Med. 24(10):1253-1260 (1997)). Nonetheless, the effect of a selective SSRI in human brain in vivo has been directly measured by [123I]β-CIT/SPECT imaging of SERT sites in depressed patients undergoing treatment with citalopram (Pirker, W. et al., J. Neural Trans. Gen Sec. 100(3):247-256 (1995)). A more selective series of compounds, nor-β-CIT (N-demethylated analog of β-CIT) (Bergstrom, K. A. et al., Eur. J. Nucl. Med. 24(6):596-601 (1997)) and related derivatives, (Blough, B. E. et al., J. Med. Chem. 40(24):3861-3864 (1997)) have recently been reported as improved SPECT imaging agents for SERT. It is suggested that [123.I]nor-β-CIT might be a suitable alternative tracer for visualization of SERT sites in the human brain with SPECT (Bergstrom, K. A. et al. Eur. J. Nucl. Med. 24(6):596-601 (1997); Hiltunen, J. et al., Eur. J. Nucl. Med. 25(1): 19-23 (1998)). However, [123I]nor-β-CIT still binds to both DAT and SERT, and the selectivity is not sufficient to distinguish between these two motioamline transporter sites. The need for a selective SERT/SPECT imaging agent is still unfulfilled. Therefore, there is a strong impetus to find an improved agent with a better selectivity for imaging SERT in the brain.
A chlorinated compound, 5-chloro-2-((2-((dimethyl-amino)methyl)phenyl)thio)benzyl alcohol (403U76), was reported as an inhibitor for serotonin uptake and norepinephrine uptake in rat brain synaptosomes (Ki=2.1 and 55 nM, respectively) (Ferris, R. M. el at, J. Pharm. Pharmacol. 47:775-781 (1995); Brieaddy, L. E., “Substituted diphenylsulfides as serotonin uptake inhibitors,” published International Patent Appl. No. WO 93/12080 (1993); Mehta, N. B. et al., “Halogen substituted diphenylsulfides,” published European Patent Application EP 402,097 A1 (1990)).